Excessive excitation by neurotransmitters can cause the degeneration and death of neurons. It is believed that this excitotoxic action is mediated by the excitatory amino acids, glutamate and aspartate, acting at the N-methyl-D-aspartate (NMDA) receptor. This action is responsible for neuronal loss in cerebrovascular disorders such as: cerebral ischemia or cerebral infarction resulting from a range of conditions such as thromboembolic or hemorrhagic stroke, cerebral vasospasm, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery, and cerebral trauma.
While there are no specific therapies for these neurodegenerative disorders, compounds acting specifically to antagonize, competitively or noncompetitively, excitatory neurotransmission at NMDA receptors offer a novel therapeutic approach to these disorders: R. Schwarcz and B. Meldrum, The Lancet 140 (1985); B. Meldrum in "Neurotoxins and Their Pharmacological Implications" edited by P. Jenner, Raven Press, New York, 1987); D. W. Choi, Neuron 1:623 (1988). Recent literature reports have confirmed the protective action of examples of noncompetitive NMDA antagonists in pharmacological models of neuro-degenerative disorders: J. W. McDonald, F. S. Silverstein, and M. V. Johnston, Eur. J. Pharmacol. 140:359 (1987); R. Gill, A. C. Foster, and G. N. Woodruff, J. Neurosci. 7:3343 (1987); S. M. Rothman, J. H. Thurston, R. E. Hauhart, G. D. Clark, and J. S. Soloman, Neurosci. 21:673 (1987); M. P. Goldbert, P-C. Pham and D. W. Choi, Neurosci. Lett. 80:11 (1987); L. F. Copeland, P. A. Boxer, and F. W. Marcoux, Soc. Neurosci. Abstr. 14 (part 1):420 (1988); J. A. Kemp, A. C. Foster, R. Gill, and G. N. Woodruff, TIPS 8:414 (1987); R. Gill, A. C. Foster, and G. N. Woodruff, J. Neurosci. 25:847 (1988); C. K. Park, D. G. Nehls, D. 1. Graham, G. M. Teasdale, and J. M. McCulloch, Ann. Neuro. 24:543 (1988); G. K. Steinberg, C. P. George, R. DeLaPaz, D. K. Shibata, and T. Gross, Stroke 19:1112 (1988); J. F. Church, S. Zeman, and D. Lodge, Anesthesiology 69:702 (1988).
U.S. Pat. Nos. 3,159,677, 3,206,480, and 3,111,527, and British Patent 893,920 disclose certain fluorenamines, dibenzofuranamines, dibenzothiophenamines, and processes for preparing them. The compounds are disclosed as having central nervous system depressant activity. The further preparation of these compounds is described by E. Godefroi and L. Simanyi in J. Org. Chem. 28:1112 (1963). U.S. Pat. No. 3,317,527 and Netherlands Patent 6,415,270 disclose certain amino substituted 5- to 7[a]-benzofuranols as central nervous system stimulants. United States Patent 4,668,690 discloses hexahydro-4a-aminoalkyldibenzofurans useful as analgesics, anticonvulsants, and antidepressants. The preparation of certain aminoethyl tetrahydrodibenzofuranamines is described by D. J. Ackland and J. T. Pinhey in J. Chem. Soc. Perkin Transl. 2695 1987). Japanese Patent 50668 discloses certain aminoethylphenanthrenes as antihypotensives. The preparation of further aminoethyl tetrahydrophenanthreneamines are described by T. Kamatani, M. Nishimura, K. Higurashi, M. Tsbuki, and Ionda in J. Org. Chem. 52:5233 (1987). The preparation of certain aminomethylhexahydrophenanthrenes and a trans ring-fused octahydrophenanthreneamine is described by J. P. Yardley and R. W. Rees in Can. J. Chem. 63:1013 (1985). None of these publications teaches to the preparation and utility of the compounds of the present invention.
The compounds of the present invention are useful in the treatment of neurodegenerative disorders including cerebrovascular disorders. Such disorders include but are not limited to cerebral ischemia or cerebral infarction resulting from a range of conditions such as thromboembolic or hemorrhagic stroke, cerebral vasospasm, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowining, pulmonary surgery, and cerebral trauma. Other treatments are for schizophrenia, epilepsy, spasticity, neurodegenerative disorders such as Alzheimer's disease or Huntington's disease, Olivo-pontocerebellar atrophy, spinal cord injury, and poisoning by exogenous NMDA poisons (e.g., some forms of lathyrism). Further uses are as analgesics and anesthetics, particularly for use in surgical procedures where a finite risk of cerebrovascular damage exists.